Crystalline Form of Telmisartan Sodium

ABSTRACT

The invention relates to a crystalline sodium salt of 4′-[2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid (INN: telmisartan), processes for preparing it and the use thereof for preparing a pharmaceutical composition.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/777,304, which isa continuation of U.S. application Ser. No. 10,283,440, filed Oct. 30,2002, which claims, as does the present application priority to U.S.Provisional Application Ser. No. 60/351,443, filed on Jan. 24, 2002, thedisclosures of all of which are incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The invention relates to a crystalline form of the sodium salt oftelmisartan, processes for preparing it and the use thereof forpreparing a pharmaceutical composition.

BACKGROUND OF THE INVENTION

Telmisartan is the nonproprietary name (INN, USAN and BAN) for4′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. It has the following chemical structure

and is known from European Patent EP 502 314 B1 and U.S. Pat. 5,591,762.

Telmisartan, and the physiologically acceptable salts thereof, havevaluable pharmacological properties. Telmisartan is an angiotensinantagonist, particularly an angiotensin-II-antagonist which by virtue ofits pharmacological properties may be used for example to treathypertension and cardiac insufficiency, to treat ischaemic peripheralcirculatory disorders, myocardial ischaemia (angina), to prevent theprogression of cardiac insufficiency after myocardial infarct, to treatdiabetic neuropathy, glaucoma, gastrointestinal diseases and bladderdiseases. Other possible therapeutic applications can be found in EP502314 B1 and U.S. Pat. 5,591,762.

A pharmaceutical formulation comprising telmisartan as the activeingredient, Micardis® (telmisartan) Tablets, is commercially available.

Starting from the free acid of telmisartan, the preparation in the formin which telmisartan is marketed is produced by a complex spray dryingprocess. Because of the limited solubility of the free acid, lesscomplex methods of preparing an alternative preparation are difficult toachieve.

Thus, one objective of the present invention is to find a less complexand easier means for preparing a crystalline form of telmisartan thatwould be suitable for use in the preparation of pharmaceuticalformulations.

It has to be borne in mind that generally the production of acomposition containing a pharmaceutically active substance is based onvarious parameters which are linked to the nature of the activeingredient itself. Without being tied thereto, examples of theseparameters are the stability of effect of the starting material underdifferent environmental conditions, the stability during the manufactureof the pharmaceutical formulation and the stability in the finalcompositions of the pharmaceutical preparation. The pharmaceuticallyactive substance used to prepare the abovementioned pharmaceuticalcompositions should be as pure as possible and its stability onlong-term storage must be guaranteed under various environmentalconditions. This is absolutely essential, in order to preventpharmaceutical compositions being used which contain, in addition to theactive substance proper, breakdown products thereof In such a case thecontent of active substance present in a preparation produced therefrommay be less than the specified amount.

Another aspect which is important in the production of solidpreparations is that the active substance should have the most stablepossible crystalline morphology for pharmaceutical quality. If this isnot the case, the morphology of the active substance may change incertain circumstances under the conditions of manufacture of thepreparation. Such a change may in turn affect the reproducibility of themanufacturing process and thus lead to final formulations which do notmeet the high quality requirements imposed on formulations ofpharmaceutical compositions. To this extent it should be generally bornein mind that any change to the solid state of a pharmaceuticalcomposition which can improve its physical and chemical stability givesa significant advantage of less stable forms of the same drug.

Thus, a further object of the invention is to provide a new, stable,crystalline form of telmisartan which complies with the abovementionedstringent requirements imposed on pharmaceutically active substances.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1: X-ray powder diagram of telmisartan-sodium salt

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that telmisartan can be obtained incrystalline form, as the sodium salt of the below formula 1.

In accordance with conventions respecting the use of nonproprietarynames, the telmisartan salt of formula 1 may be referred to astelmisartan sodium. Therefore, as used herein, the term “telmisartansodium” is defined to mean the telmisartan salt of formula 1.

By a suitable choice of manufacturing conditions, the polymorphic formof the crystalline sodium salt which meets the requirements mentionedabove can be obtained selectively.

This crystalline form of the sodium salt of telmisartan is characterisedby having a melting point of T=245±5° C. (determined by DSC=DifferentialScanning Calorimetry; heating rate: 10 K/min).

The present invention therefore relates to a crystalline form oftelmisartan sodium that is characterised by having a melting point ofT=245±5° C. (determined by DSC). The above value was obtained using aDSC821 made by Messrs Mettler-Toledo.

The crystalline form of telmisartan sodium according to the inventionwas examined more closely by x-ray powder diffraction. The X-ray powderdiagram obtained is shown in FIG. 1.

The following Table 1 summarizes the data obtained in this x-ray powderdiffraction analysis: TABLE 1 rel. intensity 2 Θ [°] d [Å] [%] 3.5424.96 7 4.21 20.95 100 4.45 19.83 20 4.98 17.72 54 5.69 15.52 8 6.3213.97 34 6.48 13.63 35 7.12 12.41 12 7.49 11.80 11 8.08 10.93 4 8.4910.41 6 8.96 9.86 7 9.50 9.31 5 10.19 8.68 5 10.80 8.18 8 11.16 7.92 1811.88 7.44 7 12.51 7.07 7 12.79 6.92 11 13.17 6.72 7 13.68 6.47 7 14.366.16 10 14.98 5.91 13 15.51 5.71 14 15.70 5.64 12 16.21 5.46 8 17.095.18 10 17.48 5.07 9 18.10 4.90 9 19.18 4.62 11 19.43 4.56 13 19.95 4.4511 20.89 4.25 11 21.29 4.17 10 22.19 4.00 9 23.07 3.85 10 23.76 3.74 924.43 3.64 8

In the above Table the value “2 Θ [°]” denotes the angle of diffractionin degrees and the value “d [Å]” denotes the lattice plane spacingsdetermined in Å.

According to the findings given in Table 1, the crystalline form oftelmisartan sodium that constitutes the invention is characterised inthat, when subjected to analysis by x-ray powder diffraction, itexhibits a characteristic set of d-spacings that includes values atd=20.95 Å, 17.72 Å, 13.97 Å and 13.63 Å.

The X-ray powder diagrams were recorded within the scope of the presentinvention using a Bruker D8 Advanced with an SSD (=site-sensitivedetector) (CuK_(α)−radiation, λ=1.5418 Å, 30 kV, 40 mA).

The present invention also comprises the solvates and hydrates of theabove-described crystalline form of telmisartan sodium, especially thehydrates, most especially the hemihydrate thereof

In another aspect, the present invention comprises a method of producingthe crystalline form of telmisartan sodium according to the invention.The starting material used to prepare the crystalline telmisartan sodiumaccording to the invention may be the free acid of telmisartan, whichmay be obtained by methods known in the art (e.g. according to EP 502314A1 and U.S. Pat. No. 5,591,762).

To prepare the crystalline telmisartan sodium according to the inventionthe free acid of telmisartan is taken up in a suitable solvent,preferably in an organic aprotic solvent, most preferably in an organic,aprotic and non-polar solvent. The solvents used according to theinvention are most preferably toluene, chloroform, dichloromethane,tetrahydrofuran, diethylether, diisopropylether, methyl-tert.butylether, acetone, methylisobutylketone, benzene or acetonitrile, ofwhich toluene, benzene and methylisobutylketone are particularlypreferred. Of outstanding importance according to the invention istoluene as solvent.

Preferably, between 0.5 and 5 ml, more preferably between 1 and 3 ml,most preferably between 1.5 and 2.5 ml of the abovementioned solvent areused per gram of telmisartan (free acid).

A suitable sodium salt is then added as a base to this solution orsuspension. Suitable sodium salts within the scope of the presentinvention include sodium hydroxide, sodium hydride, sodium carbonate,sodium hydrogen carbonate or sodium alkoxides. By sodium alkoxides aremeant the sodium salts which are formed with lower alcohols, preferablywith alcohols selected from among methanol, ethanol, isopropanol,n-propanol, tert-butanol, sec.-butanol, isobutanol, n-butanol andtert.-amylalcohol. Of particular interest according to the invention aresodium salts selected from among sodium hydroxide, sodium hydride,sodium ethoxide and sodium methoxide; of these, sodium hydroxide andsodium methoxide are of particular importance according to theinvention. The abovementioned sodium salts may be added to the reactionmixture as solids. In the case of sodium hydroxide this is preferablyadded in the form of aqueous solutions, however. It is particularlypreferable to use concentrated aqueous solutions of sodium hydroxide.For example, sodium hydroxide solution may be used in a concentration ofabout 45 wt.-%.

The amount of sodium salt to be used naturally depends on the amount offree acid telmisartan used. According to the invention at least 1 mol ofsodium salt has to be added per mol of telmisartan. It is also possibleaccording to the invention to add an excess of sodium salt. Preferably,1-2.5, more preferably 1-2, most preferably 1-1.5 mol of sodium salt areadded per mol of the acid telmisartan used.

If sodium hydroxide is used as the sodium salt and this is added in theform of an aqueous solution, according to a preferred embodiment of theprocess according to the invention, it may be helpful in some cases toadd a water-miscible organic solvent. This is preferably selected fromamong methanol, ethanol, isopropanol, acetone, tetrahydrofuran,tert.-butanol, 2-butanol, butanol, glycol, ethyldiglycol,1,3-butanediol, 1,4-butanediol, tert.-amylalcohol, acetonitrile,nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone,dimethylsulphoxide, dimethylacetamide, nitroethane andmethoxy-2-propanol, of which the abovementioned alcohols areparticularly significant. It is particularly preferred, within the scopeof the process according to the invention, to use methanol or ethanol,most preferably ethanol. Preferably, between 50 and 500 ml, morepreferably between 100 and 400 ml, most preferably between 200 and 350ml of this solvent are used per mol of telmisartan used, according tothe invention.

Then the reaction mixture may be heated to speed up the progress of thereaction. Preferably, the reaction mixture is heated to a temperatureof >40° C., most preferably to over 60° C., with thorough mixing. Themaximum temperature which may be selected is naturally determined by theboiling temperature of the solvents used. If the preferred solvents asdescribed hereinbefore are used according to the invention, the mixtureis preferably heated to over 70° C. This heating is generally carriedout for a period of from 15 minutes to 2 hours, preferably between 20minutes and one hour. Then the solution obtained is filtered and anysolid remaining in the filter is washed with one or more of theabovementioned solvents.

The filtrate obtained by the process described above is added slowly,preferably dropwise, to an organic solvent which is heated to atemperature of >40° C., preferably above 60° C., most preferably toboiling point. The solvent used is preferably an organic aproticsolvent, more preferably an organic, aprotic and non-polar solvent.Solvents which may be used according to the invention are, mostpreferably, toluene, chloroform, dichloromethane, tetrahydrofuran,diethylether, diisopropylether, methyl-tert. butylether, acetone,methylisobutylketone, benzene or acetonitrile, of which toluene, benzeneand methylisobutylketone are particularly preferred. The solvent tolueneis of exceptional importance according to the invention. At the sametime as the filtrate is added to the heated solvent, in a preferredembodiment of the invention, some of the solvent is distilled off(optionally azeotropically). After all the filtrate has been added, moresolvent (e.g. about one to two thirds of the total amount of solventadded by this stage) may optionally be removed by distillation.

The concentrated solution thus obtained is cooled, preferably to ambienttemperature, whereupon the telmisartan sodium salt crystallises out.After crystallisation is complete the crystals are separated off,optionally washed with the organic solvent mentioned above and finallydried.

In another embodiment of the invention the crystalline telmisartansodium salt according to the invention may be obtained starting from theacid addition salts of formula 2

wherein H—X denotes an acid selected from among hydrochloric acid,hydrobromic acid, toluenesulphonic acid or methanesulphonic acid. Of theabovementioned acid addition salts of formula 2 the salt wherein H-Xdenotes hydrochloric acid is of particular significance. This acidaddition salts is also referred to hereinafter as telmisartanhydrochloride.

The compounds of formula 2 may be obtained for example from tert.-butyl4′-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate(=tert.-butyl ester of telmisartan) known from the prior art bysaponification in acetic acid in the presence of the acid H—X.

In order to prepare the crystalline telmisartan sodium salt of formula 1according to the invention starting from the acid addition salts offormula 2 the following procedure may be used, according to theinvention.

The compound of formula 2 is taken up in a suitable solvent and combinedwith a suitable sodium salt.

The solvent may be water and/or a suitable alcohol, such as methanol,ethanol or isopropanol mixed with an aprotic organic solvent selectedfrom among toluene, chloroform, dichloromethane, tetrahydrofuran,diethylether, diisopropylether, methyl-tert. butylether, acetone,methylisobutylketone, benzene and acetonitrile. It is particularlypreferred to use, as the solvent, water mixed with ethanol orisopropanol mixed with an aprotic organic solvent selected from amongtoluene, benzene and methylisobutylketone, most preferably toluene. Amixture of water, isopropanol and toluene has proved particularlysuitable for this step of the synthesis.

The amount of solvent or solvent mixture used depends on the amount ofacid addition salt 2 used. Preferably, about 0.3-3.5 L, preferably about1-2.5 L, more preferably about 1.5-2 L of the abovementioned solvent orsolvent mixture are used per mol of compound 2 used. If the solvent usedis the preferred solvent mixture according to the invention whichcontains an alcohol as the third solvent component in addition to waterand an aprotic organic solvent, the ratios by volume of water to aproticorganic solvent according to the invention are preferably in a rangefrom 1:5 to 1:50 and the ratio of water to alcohol used is in a rangefrom 2:1 to 1:40. Preferably, in a solvent mixture of this kind, theratios of water to aprotic organic solvent are in the range from 1:10 to1:30, preferably in the range from 1:15 to 1:25 and the ratio of waterto alcohol used is in a range from 1:1 to 1:20, preferably in the rangefrom 1:5 to 1:15.

Preferably, the solvent or solvent mixture mentioned above containsabout 10 to 100 ml of water, preferably about 30 to 80 ml of water, mostpreferably about 40 to 70 ml of water, per mol of 2. Preferably thesolvent or solvent mixture used also contains about 100 to 1000 ml ofalcohol, preferably about 300 to 800 ml alcohol, most preferably about400 to 700 ml alcohol, per mol of 2. Finally, the solvent or solventmixture used preferably contains as the third component of the solvent,about 200 to 2000 ml of the abovementioned aprotic organic solvent,preferably about 600 to 1600 ml, most preferably about 800 to 1400 ml ofthe abovementioned aprotic organic solvent, per mol of 2.

Suitable sodium salts which may be used for reacting 2 to 1 includesodium hydroxide, sodium hydride, sodium carbonate, sodium hydrogencarbonate or sodium alkoxides. By sodium alkoxides are meant the sodiumsalts which are formed with lower alcohols, preferably with alcoholsselected from among methanol, ethanol, isopropanol, n-propanol,tert-butanol, sec.-butanol, isobutanol, n-butanol and tert.-amylalcohol.Of particular interest according to the invention are sodium saltsselected from among sodium hydroxide, sodium hydride, sodium ethoxideand sodium methoxide, while the sodium alkoxides sodium ethoxide andsodium methoxide, particularly sodium methoxide are of particularimportance according to the invention for this reaction step. Theabovementioned sodium salts may be added to the reaction mixture assolids. In the case of sodium methoxide however it is preferable to addit in the form of a methanolic solution. Methanolic solutions of sodiummethoxide which contain it in a concentration of at least 10%, mostpreferably about 20-40% (w/w), are particularly preferred. For example,the methanolic sodium methoxide solution used may have a concentrationof about 30 wt. %.

The amount of sodium salt to be used is naturally dependent on theamount of free acid telmisartan used. According to the invention, atleast 2 mol of sodium salt have to be added per mol of telmisartan acidaddition salt of formula 2 used. According to the invention it is alsopossible to add an excess of sodium salt.

It may be useful in some cases to add activated charcoal to theabovementioned reaction mixture. For example, it may be added in anamount of about 5-50 g per mol of 2 used, preferably in an amount ofabout 10-40 g per mol of 2 used.

After the sodium salt and optionally the activated charcoal has beenadded the reaction mixture obtained is heated to a temperature of about50-100° C., preferably about 60-90° C., most preferably about 70-80° C.for a period of about 10 minutes to 2 hours, preferably for about 20-45minutes. In the course of this heating, some of the solvent, preferablyabout 10-50%, most preferably about 20-40% of the total quantity ofsolvent may be distilled off.

The remaining suspension is then filtered, the filter residue isoptionally washed with one of the abovementioned aprotic organicsolvents, preferably with the aprotic organic solvent which is also usedin the reaction.

The filtrate obtained is then diluted with a solvent or mixture ofsolvents. It is preferable to use a mixture of water and theabovementioned aprotic organic solvent for this. Preferably, at thispoint, about 10 to 100 ml of water, preferably about 30 to 80 ml ofwater, most preferably about 40 to 70 ml of water are used per mol ofthe compound 2 originally used. At this point, 250 to 3000 ml,preferably about 800 to 2000 ml, most preferably about 1200 to 1800 mlof aprotic organic solvent are used per mole of the compound 2originally used.

After dilution, the mixture obtained is refluxed. Then about 1-2 L,preferably about 1200 to 1800 ml of solvent are distilled off per moleof the compound 2 originally used. After the solvent has been distilledoff the telmisartan-sodium salt 1 according to the inventioncrystallises out. The crystals obtained are isolated, optionally washedwith one of the abovementioned aprotic organic solvents and then dried.

In another aspect the present invention relates to crystallinetelmisartan-sodium salt, optionally in the form of the solvates orhydrates thereof, preferably in the form of the hydrates thereof, mostpreferably in the form of the hemihydrate, which may be obtained by themethods described above.

Because of the central significance of the compounds of formula 2 asvaluable starting materials for the direct synthesis of thetelmisartan-sodium salt 1 according to the invention, in another aspectthe present invention relates to compounds of formula 2 per se

wherein H—X denotes an acid selected from among hydrochloric acid,hydrobromic acid, toluenesulphonic acid or methanesulphonic acid. Thecompound of formula 2 wherein H—X denotes hydrogen chloride, thetelmisartan hydrochloride, is particularly preferred.

Most preferably, the present invention further relates to theabovementioned compounds of formula 2 in crystalline form.

Moreover, in view of the pharmaceutical activity of the crystallinetelmisartan sodium salt according to the invention, the presentinvention relates to the use thereof as a pharmaceutical composition.

In another aspect, in view of the pharmaceutical activity of thecrystalline telmisartan sodium salt according to the invention, thepresent invention relates to the use thereof for preparing apharmaceutical composition, particularly for preparing a pharmaceuticalcomposition for the prevention or treatment of diseases wherein theadministration of therapeutically effective doses of one or moreangiotensin-II-antagonists may provide a therapeutic benefit.Preferably, the present invention relates to the use of crystallinetelmisartan-sodium salt for preparing a pharmaceutical composition forthe prevention or treatment of diseases selected from amonghypertension, cardiac insufficiency, ischaemic peripheral circulatorydisorders, myocardial ischaemia (angina), the progression of cardiacinsufficiency after myocardial infarct, diabetic neuropathy, glaucoma,gastrointestinal diseases and bladder diseases, the prevention ortreatment of hypertension being particularly preferred.

Accordingly, in another aspect, the present invention is directed topharmaceutical formulations characterised in that they containcrystalline telmisartan-sodium salt.

The example of synthesis that follows serves to illustrate a method ofpreparing crystalline telmisartan-sodium salt carried out by way ofexample. It is intended solely as a possible procedure provided by wayof example, without restricting the invention to its contents.

SYNTHESIS EXAMPLE 1

Preparation of Crystalline Telmisartan-Sodium Salt Starting fromTelmisartan

The starting material used to prepare crystalline telmisartan-sodiumsalt according to the invention may be the free acid, which may beobtained by methods known from the prior art (e.g. according to EP502314 A1).

154.4 g of telmisartan are placed in 308.8 ml of toluene in a suitablereaction vessel. The suspension is combined with 27.8 g of 44.68% sodiumhydroxide solution and 84.9 ml of ethanol and heated to 78° C. for about30 min, then the mixture is filtered. If desired, if large amounts ofsolid are left in the filter, this may be washed with a mixture of 61.8ml of toluene and 15.3 ml of ethanol.

463.2 ml of toluene are placed in another reaction vessel and refluxed.The filtrate obtained by the process described above is slowly addedthereto at boiling temperature and simultaneously distilled offazeotropically. After it has all been added the solution which may havebeen obtained from washing the filter is also added and again distilledoff azeotropically. The mixture is distilled at up to 103° C. and thesuspension is allowed to cool to ambient temperature. The crystals aresuction filtered, washed with 154.4 ml of toluene and dried at 60° C. inthe circulating air drier.

Yield: 154.6 g (96%) of colourless crystals; C₃₃H₂₉N₄O₂Na × 0.5H₂Ocalc.: C 72.51 H 5.72 N 10.25 found: C 72.57 H 5.69 N 10.21

SYNTHESIS EXAMPLE 2 Preparation of Crystalline Telmisartan-Sodium SaltStarting from Telmisartan Hydrochloride

A) Preparation of Telmisartan-Hydrochloride:

411 g of tert.-butyl4′-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateare suspended in 822 ml of glacial acetic acid and combined with 213 gof concentrated aqueous hydrochloric acid (37%). The mixture is refluxedand about 640 ml of solvent are distilled off. The residue remaining isslowly combined with about 620 ml of water at 50-60° C. To this mixtureare added 20 g of activated charcoal (e.g. Norit SX 2 Ultra) and theresulting mixture is stirred for about 10 min at constant temperature.After filtering, the residue is washed three times with 25 ml of glacialacetic acid and about 620 ml of water. The filtrate obtained is againheated to about 50-60° C. and about 2 L of water are added. Afterstirring for about 12 hours at about 23° C. the crystals formed aresuction filtered and washed twice with about 500 ml of water, once withabout 900 ml of acetone and then dried at about 60° C.

Yield: 367 g (92.5%), colourless crystals, melting point:=278° C.

B) Preparation of Crystalline Telmisartan Sodium Salt from TelmisartanHydrochloride

55.1 g of telmisartan hydrochloride are taken up in 110.2 ml of toluene,5.5 ml of water, 55.1 ml of isopropanol and this mixture is combinedwith 36.9 g of sodium methoxide (30% in methanol) and 2.75 g ofactivated charcoal (e.g. Sorit SX 2 Ultra). The mixture is then heatedto about 75° C., and about 50 ml of solvent mixture are distilled off atconstant temperature over about 30 min. The suspension obtained isfiltered and the residue is washed with about 20 ml of toluene. Thefiltrate is combined with about 5 ml of water and about 150 ml oftoluene. The mixture obtained is refluxed. During this time about 150 mlof solvent mixture are azeotropically distilled off (at up to 102° C.).The mixture is left to crystallise for one hour at 100° C. The crystalsare suction filtered, washed with about 50 ml of toluene and dried atabout 60° C.

Yield: 53.6 g (99%), colourless crystals C₃₃H₂₉N₄O₂Na 0.5H₂O calc.: C72.51 H 5.72 N 10.25 found: C 72.44 H 5.68 N 10.20

To prepare a pharmaceutical composition containing the active substance,particularly an orally administered pharmaceutical composition, mostpreferably a tablet, procedures known in the art may be used.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such asmaize starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

The following are some examples of pharmaceutical preparations which maybe used according to the invention. They are intended purely asillustrations by way of example without restricting the subject matterof the invention thereto. Tablet 1 Ingredients mg Telmisartan-sodiumsalt hemihydrate 1.00 Mannitol 121.50 Maize starch 79.85 Highlydispersed silicon dioxide, anhydrous 2.30 Polyvidon K25 2.35 Magnesiumstearate 3.00 Total 210.00

Tablet 2 Ingredients mg Telmisartan-sodium salt hemihydrate 0.50Mannitol 122.00 Maize starch, dried 61.80 Maize starch 18.00 Highlydispersed silicon dioxide, anhydrous 2.40 Polyvidon K25 2.30 Magnesiumstearate 3.00 Total 210.00

Tablet 3 Ingredients mg Telmisartan-sodium salt hemihydrate 0.25Mannitol 61.00 Maize starch 39.90 Highly dispersed silicon dioxide,anhydrous 1.20 Polyvidon K25 1.15 Magnesium stearate 1.50 Total 105.00

1. A compound of formula 2

wherein H—X denotes an acid selected from the group consisting ofhydrochloric acid, hydrobromic acid, toluenesulphonic acid andmethanesulphonic acid.
 2. The compound of formula 2 according to claim1, wherein H—X denotes hydrogen chloride.
 3. A compound according toclaim 1 or claim 2, in crystalline form.